Ranolazine, also known as 1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine; and N-(2,6-Dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazine-1-acetamide is a partial fatty acid oxidation (PFOX) inhibitor. Its synthesis is described in U.S. Pat. No. 4,567,264.
Ranolazine is an orally dosed compound with anti-anginal and anti-ischemic effects without reductions in heart rate or blood pressure. Its mechanism of action is not known, but it is believed to be an ion channel inhibitor (see Pharmacology Review CDER Approval Package for Application Number NDA 21-526 and Antzelevitch, C et al., Circulation 2004, 110, p. 904-910), even though there is no clear understanding of the electrophysiology of the compound and its efficacy in stable angina. Recent publications have reported data supporting ranolazine as an inhibitor of late sodium current, which could explain its cardiovascular activity (see Undrovinas, A I et al, J Cardiovasc Electrophysiol 2006, 17:S169; Hale S L et al, J Pharmacol Exp Ther 2006, 31:418 and Fredj S et al, Br J Pharmacol 2006, 148:16).
Ranolazine has been evaluated in clinical trials for patients with chronic angina who remain symptomatic despite treatment with the maximum dose of another anti-angina agent. Statistically significant reductions in angina attack frequency and nitroglycerine use have been shown clinically. Clinical studies have also shown statistically significant increases in exercise duration and time to angina. See Stone P H et al., J Am Coll Cardiol 2006, 48, 566; Chaitman, B R et al., Circulation 2002, 106(19, Suppl. 2): Abst 1649; and the label approved for NDA no. 021526, Drugs@FDA.gov website.
Ranolazine has been approved for treatment of chronic angina in patients who have not achieved adequate response with other anti-anginal drugs. It is approved for use in combination with other anti-anginal drugs, including calcium channel blockers, beta-blockers, and nitrates. It is also currently in phase III trials in the US for treatment of unstable angina (acute coronary syndrome).
Despite the beneficial activities of ranolazine, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.